Neurons fire when sodium channels clustered at the axonal initial segment (AIS) open. This depolarization is propagated by more channels clustered along axons in the Nodes of Ranvier (NR). The structure of these compartments is now shown to rely on a spectrin, relatives of which are needed for the characteristic concave shape of the red blood cell plasma membrane.
The AIS and NR are rich in two spectrins: βIVΣ1 and βIVΣ6. But loss of the βIVΣ1 isoform was sufficient to disrupt AIS and NR physiology. NRs in the mutants were longer and fatter and lacked the protein-dense region beneath the NR membrane, which probably corresponds to the βIVΣ1 scaffold. These changes interfered with membrane potential generation and propagation, thus causing deafness.
Recent results showed that sodium channels are concentrated in the AIS because of both anchoring to the AIS cytoskeleton and endocytosis elsewhere. The specialized AIS cytoskeleton may prevent endocytosis at this site. In the βIVΣ1 mutants, the NR contained membrane protrusions that were filled with vesicular organelles. If spectrins are involved in membrane trafficking, as has been proposed, the vesicles may be a result of increased endocytosis in the mutant NR. ▪